Low levels of high density lipoprotein (HDL) are a powerful predictor for identifying persons who are at risk for atherosclerosis. Moreover HDL is an important target for pharmacologic intervention to reduce this risk. This grant will focus on the cellular efflux properties of the major protein of HDL, apolipoprotein AI (apoAI). Plasma HDL levels do not control the rate of cellular cholesterol efflux. Instead, efflux occurs in extracellular spaces. 2 events dictate the rate of movement of cholesterol out of peripheral cells: an energy-dependent transport of cholesterol out of the cell, a process carried out by ABCA1; and the availability of a lipid-poor acceptor of this transported cholesterol, an amphipathic alpha helical apoprotein. Studies in vitro have verified that many apoproteins including apoproteins AI, All, AIV and E are equally good acceptors of cellular cholesterol. Only apoAI will mediate macrophage (Mphi)-mediated lipid efflux from foam cells within atherosclerotic lesions. This proposal will test the hypothesis that this in vivo specificity for apoAI is a function of the ability of apoAI to dissociate from spherical alpha-migrating HDL and form transiently stable, lipid-poor apoAI. Our studies are performed in low density lipoprotein receptor-deficient (LDLr-/-) mice and involve 3 specific aims. The first aim will identify the role of phospholipid transfer protein (PLTP) in the generation of lipid-poor apoAI in vivo and in vitro. The second aim will identify the role played by cholesterol ester transfer protein (CETP) in this same process. Both of these transfer proteins are expressed in Mphi, can generate lipid-poor apoAI from spherical HDL and are induced by ligation of nuclear liver X receptors (LXR). The third aim will identify the role of lipoprotein lipase (LpL) and hepatic lipase (HL) in the generation of lipid-poor apo AI. These lipases also are expressed by Mphi and regulated by LXR. We propose that core lipid reduction by triglyceride hydrolysis and remodeling by PLTP and CETP release lipid-poor apoAI from HDL to facilitate efflux from Mphi foam cells within atherosclerotic lesions.